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The intratumoral immune cytolytic activity (CYT) reflects the ability of cytotoxic T and NK cells to eliminate cancer cells, and is associated with improved patient survival. Despite the enthusiastic clinical results seen in advanced-stage metastatic melanoma patients treated with immune checkpoint inhibitors, a subgroup of them will later relapse and develop acquired resistance. We questioned whether CYT associates with different genomic profiles\u00a0and thus, patient outcome, in skin melanoma.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We explored the TCGA-SKCM dataset and stratified patients to distinct subgroups of cytolytic activity. The tumor immune contexture, somatic mutations and recurrent copy number aberrations were calculated using quanTIseq, MutSigCV and GISTIC2. Chromothriptic events were explored using CTLPScanner and cancer neoepitopes were predicted with antigen garnish. Each tumor's immunophenoscore was calculated using Immunophenogram. Mutational signatures and kataegis were explored using SigProfiler and compared to the known single or doublet base substitution signatures from COSMIC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Metastatic skin melanomas had significantly higher CYT levels\u00a0compared to primary tumors. We assessed enrichment for immune-related gene sets within CYT-high tumors, whereas, CYT-low tumors were enriched for non-immune related gene sets. In addition, distinct mutational and neoantigen loads, primarily composed of C\u2009&gt;\u2009T transitions, along with specific types of copy number aberrations, characterized each cytolytic subgroup. We found a broader pattern of chromothripsis across CYT-low tumors, where chromosomal regions harboring\u00a0chromothriptic events, contained a higher number of cancer genes. SBS7a\/b, SBS5 and SBS1 were the most prevalent mutational signatures across both cytolytic subgroups, but SBS1 differed significantly between them. SBS7a\/b was mutually exclusive with SBS5 and SBS1 in both CYT subgroups. CYT-high patients had markedly higher immunophenoscore, suggesting that they should display\u00a0a clinical benefit\u00a0upon treatment with immune checkpoint inhibition therapy, compared to CYT-low patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Overall, our data highlight the existence of distinct genomic features across cytolytic subgroups in skin melanoma, which\u00a0might affect the patients' relapse rate or their\u00a0acquisition of resistance to immune checkpoint inhibition therapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00262-021-02918-3","type":"journal-article","created":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T08:02:31Z","timestamp":1617004951000},"page":"3137-3154","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Distinct genomic features across cytolytic subgroups in skin melanoma"],"prefix":"10.1007","volume":"70","author":[{"given":"Constantinos","family":"Roufas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilias","family":"Georgakopoulos-Soares","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4625-5562","authenticated-orcid":false,"given":"Apostolos","family":"Zaravinos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,29]]},"reference":[{"key":"2918_CR1","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1038\/35020115","volume":"406","author":"M Bittner","year":"2000","unstructured":"Bittner M et al (2000) Molecular classification of cutaneous malignant melanoma by gene expression profiling. 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